The research addresses how photoreceptor neurons withdraw permanently from the cell cycle, and the relationships of cell cycle withdrawal to both neural degeneration and to cancer. A new hypothesis is proposed that relates cell cycle withdrawal to the axonal structure of photoreceptor neurons, and to their survival. The eye of the fruit fly Drosophila melanogaster will be used to evaluate this new hypothesis, and to identify specific aspects of cell cycle progression, or of postmitotic structure, that trigger neuronal loss, as well as to search for novel, unknown genes that influence these events. These objectives will be achieved by using transgenic fruit flies and molecular genetic techniques to target RNAs and proteins to specific subsets of photoreceptor cells in a conditional manner. In this way, components of the cell cycle, cytoskeleton, and multiple cell death pathways will be manipulated to determine their effects on the maintenance of cell cycle quiescence, on the structure of photoreceptor cells and especially their axons, and on the cell-autonomous and non-autonomous mechanisms of photoreceptor cell survival. The information obtained in this study is expected to guide approaches to reduce proliferation of retinoblastoma, to minimize neuronal loss in some retinal degeneration, and possibly to reduce neuronal loss in other neurodegenerative conditions such as Alzheimer's Disease, Amylotrophic Lateral Sclerosis, Huntington's Disease, Charcot-Marie Tooth Disease, hereditary spastic paraplegia SPG10, Spinocerebellar Ataxia type 5, Fronto-temporal Dementia, certain viral encephalitis syndromes, Parkinson's Disease, and stroke. PUBLIC HEALTH RELEVANCE: The proposal explores a novel hypothesis connecting cell proliferation in the nervous system to nerve cell structure and to neuron degeneration. The studies make use of the eye of the fruit fly Drosophila melanogaster. The results will be useful for the design of new approaches to treating retinoblastoma, retinal degeneration, and neurodegenerative conditions.